The objective of this study is to generate clinically relevant models of optic neuropathy in a species that recapitulates the anatomy and physiology of the human retina and optic nerve that can be used to optimize allogenic transplantation of induced pluripotent stem cell (iPSC)-derived retinal ganglion cells (RGCs). We will use the tree shrew, which has a collagenous, load-bearing lamina cribrosa and a cone-dominant retina with fovea-level convergence onto the RGCs. We will induce and characterize two optic neuropathies in this species, glaucoma and traumatic optic neuropathy. Simultaneously, we will optimize generation of tree shrew optic cup organoids from fibroblasts as the source of allogenic RGCs for transplantation. We will compare the transcriptome profile of these induced RGCs to primary tree shrew RGCs. We will optimize transplantation of these cells in both models by identifying: 1) the optimal disease stage for transplantation, 2) the optimal differentiation stage of the RGCs for transplantation, 3) if modulating the inner limiting membrane will improve integration, and 4) if co-treatment a zinc chelator will improve axon outgrowth of the transplanted retinal ganglion cells. In characterizing the two models we will quantify changes in cytokine levels, glial reactivity, axon degeneration, and RGC death over time. Our primary outcomes for the transplantation studies will be functional: pattern electroretinograms, in vivo calcium imaging, and ex vivo microelectrode recordings. Secondary outcomes for will include quantification of surviving transplanted cells located within the ganglion cell layer, the length of axons, and dendrite formation and synaptic connectivity with upstream neurons.